Department of Neurosurgery, UCSF, San Francisco, California, USA.
Department of Bioengineering, UC Berkeley, Berkeley, California, USA.
J Clin Invest. 2023 Nov 16;134(3):e170397. doi: 10.1172/JCI170397.
While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site-directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site-directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.
虽然神经胶质瘤的预后不良是由于肿瘤细胞的一部分侵袭所致，但对于这些细胞内促进侵袭的代谢改变知之甚少。我们整合了空间可寻址水凝胶生物材料平台、患者导向活检和多组学分析，以确定侵袭性神经胶质瘤细胞的代谢驱动因素。代谢组学和脂质组学揭示了在水凝胶培养的肿瘤和患者导向活检的侵袭前沿中，氧化还原缓冲剂胱硫醚、己糖神经酰胺和葡萄糖神经酰胺以及免疫荧光显示侵袭细胞中活性氧（ROS）标志物升高。转录组学证实了在水凝胶模型和患者肿瘤的侵袭前沿中，ROS 产生和反应基因的上调。在肿瘤相关 ROS 中，H2O2 特异性促进了 3D 水凝胶球体培养物中的神经胶质瘤侵袭。CRISPR 代谢基因筛选显示胱硫醚γ-裂解酶（CTH）在转硫途径中将胱硫醚转化为非必需氨基酸半胱氨酸，对于神经胶质瘤的侵袭是必需的。相应地，用外源性半胱氨酸补充 CTH 敲低细胞可挽救侵袭。药理 CTH 抑制抑制神经胶质瘤侵袭，而 CTH 敲低可减缓体内神经胶质瘤侵袭。我们的研究强调了 ROS 代谢在侵袭性神经胶质瘤细胞中的重要性，并支持进一步探索转硫途径作为一种机制和治疗靶点。
